The invention relates to a group of aminoheterocyclic derivatives, or pharmaceutically-acceptable salts thereof, which possess antithrombotic and anticoagulant properties and are accordingly useful in methods of treatment of the human or animal body. The invention also relates to processes for the preparation of said aminoheterocyclic derivatives, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments for use in the production of an antithrombotic or anticoagulant effect.
The antithrombotic and anticoagulant effect produced by the compounds of the invention is believed to be attributable to their strong inhibitory effect against the activated coagulation protease known as Factor Xa. Factor Xa is one of a cascade of proteases involved in the complex process of blood coagulation. The protease known as thrombin is the final protease in the cascade and Factor Xa is the preceding protease which cleaves prothrombin to generate thrombin.
Certain compounds are known to possess Factor Xa inhibitory properties and the field has been reviewed by R. B. Wallis, Current Opinion in Therapeutic Patents, 1993, 1173-1179. Thus it is known that two proteins, one known as antistatin and the other known as tick anticoagulant protein (TAP), are specific Factor Xa inhibitors which possess antithrombotic properties in various animal models of thrombotic disease.
It is also known that certain non-peptidic compounds possess Factor Xa inhibitory properties. Of the low molecular weight inhibitors mentioned in the review by R. B. Wallis, all possessed a strongly basic group such as an amidinophenyl or amidinonaphthyl group.
It is the object of the present invention to provide a new class of agent which lacks the amidino group previously believed to be an essential feature for a Factor Xa inhibitor.
We have now found that certain amino-substituted heterocyclic derivatives possess Factor Xa inhibitory activity. Many of the compounds of the present invention also possess the advantage of being selective Factor Xa inhibitors, that is the enzyme Factor Xa is inhibited strongly at concentrations of test compound which do not inhibit or which inhibit to a lesser extent the enzyme thrombin which is also a member of the blood coagulation enzymatic cascade.
The compounds of the present invention possess activity in the treatment or prevention of a variety of medical disorders where anticoagulant therapy is indicated, for example in the treatment or prevention of thrombotic conditions such as coronary artery and cerebro-vascular disease. Further examples of such medical disorders include various cardiovascular and cerebrovascular conditions such as myocardial infarction, the formation of atherosclerotic plaques, venous or arterial thrombosis, coagulation syndromes, vascular injury including reocclusion and restenosis following angioplasty and coronary artery bypass surgery, thrombus formation after the application of blood vessel operative techniques, the introduction of artificial heart valves or on the recirculation of blood, cerebral infarction, cerebral thrombosis, stroke, cerebral embolism, pulmonary embolism, ischaemia and angina (including unstable angina).
The compounds of the invention are also useful as inhibitors of blood coagulation in an ex-vivo situation such as, for example, the storage of whole blood or other biological samples suspected to contain Factor Xa and in which coagulation is detrimental.
According to one aspect of the invention there is provided an aminoheterocyclic derivative of the formula I (set out hereinafter) wherein G1 is CH or N;
G2 is CH or N;
G3 is CH or N;
m is 1 or 2;
R1 is hydrogen, amino, halogeno, cyano, (1-4C)alkyl or (1-4C)alkoxy;
M1 is a group of the formula
NR2xe2x80x94L1xe2x80x94T1R3 
in which R2 and R3 together form a (1-4C)alkylene group,
L1 is (1-4C)alkylene, and
T1 is CH or N,
and wherein 1 or 2 methylene groups within L1 and the ring formed when R2 and R3 are linked optionally bears a (1-4C)alkyl substituent;
A is a direct link to the carbonyl group, or A is (1-4C)alkylene;
M2 is a group of the formula
(T2R4)rxe2x80x94L2xe2x80x94T3R5 
in which r is 0 or 1,
T2 is CH or N,
T3 is CH or N,
R4 is hydrogen or (1-4C)alkyl, R5 is hydrogen or (1-4C)alkyl, or R4 and R5 together form a (1-4C)alkylene, methylenecarbonyl or carbonylmethylene group, or R4 is a (2-3C)alkylene group which is linked to a methylene group within L2 forming a 5- or 6-membered ring involving R4 and T2, or R5 is a (2-3C)alkylene group which is linked to a methylene group within L2 forming a 5- or 6-membered ring involving R5 and T3,
L2 is (1-4C)alkylene, (3-6C)cycloalkane-1,2-diyl, (1-3C)alkylene-carbonyl or phenylene, and, when r is 1, L2 may also be carbonyl-(1-3C)alkylene, and wherein 1 or 2 methylene groups within L2 and the rings formed when R4 and R5, R4 and L2 or R5 and L2 are linked optionally bears a substituent selected from the group consisting of oxo, carboxy, (1-4C)alkoxycarbonyl, carbamoyl, N-(1-4C)alkylcarbamoyl, N,N-di-(1-4C)alkylcarbamoyl, pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl, 4-(1-4C)alkylpiperazin-1-ylcarbonyl, N-phenylcarbamoyl N-(1-4C)alkyl-N-phenylcarbamoyl, N-[phenyl-(1-3C)alkyl]carbamoyl, N-(1-4C)alkyl-N-[phenyl-(1-3C)alkyl]carbamoyl, N-[hydroxy-(2-3C)alkyl]carbamoyl, N-(1-4C)alkyl-N-[hydroxy-(2-3C)alkyl]carbamoyl, N-[(1-4C)alkoxy-(2-3C)alkyl]carbamoyl, N-(1-4C)alkyl-N-[(1-4C)alkoxy-(2-3C)alkyl]carbamoyl, N-[carboxy-(1-3C)alkyl]carbamoyl, N-(1-4C)alkyl-N-[carboxy-(1-3C)alkyl]carbamoyl, N-[carboxy-(1-3C)alkyl]-N-[hydroxy-(2-3C)alkyl]carbamoyl, N-[carboxy-(1-3C)alkyl]-N-[(1-4C)alkoxy-(2-3C)alkyl]carbamoyl, N-[(1-4C)alkoxycarbonyl-(1-3C)alkyl]carbamoyl, N-(1-4C)alkyl-N-[(1-4C)alkoxycarbonyl-(1-3C)alkyl]carbamoyl, N-[(1-4C)alkoxycarbonyl-(1-3C)alkyl]-N-[hydroxy-(2-3C) alkyl]carbamoyl, N-[(1-4C)alkoxycarbonyl-(1-3C) alkyl]-N-[(1-4C)alkoxy-(2-3C)alkyl]carbamoyl, (1-4C)alkyl, carboxy-(1-4C)alkyl, (1-4C)alkoxycarbonyl-(1-4C)alkyl, carbamoyl-(1-4C)alkyl, N-(1-4C)alkylcarbamoyl-(1-4C)alkyl, N,N-di-(1-4C)alkylcarbamoyl-(1-4C)alkyl, pyrrolidin-1-ylcarbonyl-(1-4C)alkyl, piperidinocarbonyl-(1-4C)alkyl, morpholinocarbonyl-(1-4C)alkyl, piperazin-1-ylcarbonyl-(1-4C)alkyl, 4-(1-4C)alkylpiperazin-1-ylcarbonyl-(1-4C)alkyl, N-phenylcarbamoyl-(1-4C)alkyl, N-[phenyl-(1-3C)alkyl]carbamoyl-(1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl and phenyl-(1-4C)alkyl,
and wherein any heterocyclic group in said substituent optionally bears 1 or 2 substituents selected from the group consisting of (1-4C)alkyl, (1-4C)alkoxy, carboxy, (1-4C)alkoxycarbonyl, carbamoyl, N-(1-4C)alkylcarbamoyl and N,N-di-(1-4C)alkylcarbamoyl,
and wherein any phenyl or phenylene group in M2 optionally bears 1 or 2 substituents selected from the group consisting of halogeno, trifluoromethyl, (1-4C)alkyl and (1-4C)alkoxy;
M3 is a direct link to X, or M3 is a group of the formula
L3xe2x80x94(NR6)s 
in which s is 0 or 1,
R6 is hydrogen or (1-4C)alkyl, or R5 and R6 together form a (1-4C)alkylene, methylenecarbonyl or carbonylmethylene group, or R6 is a (2-3C)alkylene group which is linked to a methylene group within L3 forming a 5- or 6-membered ring involving NR6,
L3 is (1-4C)alkylene, (3-6C)cycloalkane-1,2-diyl, carbonyl-(1-3C)alkylene or phenylene, and, when s is 1, L3 may also be (1-3C)alkylene-carbonyl,
and wherein 1 or 2 methylene groups within L3 and the rings formed when R5 and R6 or R6 and L3 are linked optionally bears a substituent selected from the group consisting of oxo, carboxy, (1-4C)alkoxycarbonyl, carbamoyl, N-(1-4C)alkylcarbamoyl, N,N-di-(1-4C)alkylcarbamoyl, pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl, 4-(1-4C)alkylpiperazin-1-ylcarbonyl, N-phenylcarbamoyl, N-(1-4C)alkyl-N-phenylcarbamoyl, N-[phenyl-(1-3C)alkyl]carbamoyl, N-(1-4C)alkyl-N-[phenyl-(1-3C)alkyl]carbamoyl, (1-4C)alkyl, carboxy-(1-4C)alkyl, (1-4C)alkoxycarbonyl-(1-4C)alkyl, carbamoyl-(1-4C)alkyl, N-(1-4C)alkylcarbamoyl-(1-4C)alkyl, N,N-di-(1-4C)alkylcarbamoyl-(1-4C)alkyl, pyrrolidin-1-ylcarbonyl-(1-4C)alkyl, piperidinocarbonyl-(1-4C)alkyl, morpholinocarbonyl-(1-4C)alkyl, piperazin-1-ylcarbonyl-(1-4C)alkyl, 4-(1-4C)alkylpiperazin-1-ylcarbonyl-(1-4C)alkyl, N-phenylcarbamoyl-(1-4C)alkyl, N-[phenyl-(1-3C)alkyl]carbamoyl-(1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl and phenyl-(1-4C)alkyl,
and wherein any heterocyclic group in said substituent optionally bears 1 or 2 substituents selected from the group consisting of (1-4C)alkyl, (1-4C)alkoxy, carboxy, (1-4C)alkoxycarbonyl, carbamoyl, N-(1-4C)alkylcarbamoyl and N,N-di-(1-4C)alkylcarbamoyl,
and wherein any phenyl or phenylene group in M3 optionally bears 1 or 2 substituents selected from the group consisting of halogeno, trifluoromethyl, (1-4C)alkyl and (1-4C)alkoxy;
X is oxy, thio, sulphinyl, sulphonyl, carbonyl, carbonyloxy, carbonylamino, N-(1-4C)alkylcarbonylamino, sulphonylamino, methylene, (1-4C)alkylmethylene or di-(1-4C)alkylmethylene, or, when T3 is CH and M3 is a direct link to X, X may also be aminosulphonyl or oxycarbonyl; and
Q is phenyl, naphthyl, phenyl-(1-4C)alkyl, phenyl-(2-4C)alkenyl, phenyl-(2-4C)alkynyl, (5-7C)cycloalkyl or a heterocyclic moiety containing up to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur, and Q optionally bears 1, 2 or 3 substituents selected from the group consisting of hydroxy, amino, halogeno, cyano, trifluoromethyl, nitro, carboxy, carbamoyl, formyl, formimidoyl, formohydroximoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl, (1-4C)alkoxy, N-(1-4C)alkylcarbamoyl, N,N-di-(1-4C)alkylcarbamoyl, (1-4C)alkylamino, di-(1-4C)alkylamino, (2-4C)alkanoylamino, (2-4C)alkanoyl, (2-4C)alkanoimidoyl, (2-4C)alkanohydroximoyl, phenyl, heteroaryl, phenoxy, phenylthio, phenylsulphinyl, phenylsulphonyl, heteroaryloxy, heteroarylthio, heteroarylsulphinyl, heteroarylsulphonyl, benzyl and benzoyl,
and wherein said heteroaryl substituent or the heteroaryl group in a heteroaryl-containing substituent comprises a 5- or 6-membered monocyclic heteroaryl ring containing up to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur, and wherein said phenyl, heteroaryl, phenoxy, phenylthio, phenylsulphinyl, phenylsulphonyl, heteroaryloxy, heteroarylthio, heteroarylsulphinyl, heteroarylsulphonyl, benzyl or benzoyl substituent optionally bears 1, 2, 3 or 4 substituents selected from the group consisting of halogeno, trifluoromethyl, cyano, trifluoromethoxy, nitro, (1-4C)alkyl, (1-4C)alkoxy, hydroxy, amino, carboxy, carbamoyl, (1-4C)alkoxycarbonyl, N-(1-4C)alkylcarbamoyl, N,N-di-(1-4C)alkylcarbamoyl, (1-4C)alkylamino, di-(1-4C)alkylamino, (2-4C)alkanoylamino and tetrazolyl;
or a pharmaceutically-acceptable salt thereof.
The chemical formulae referred to herein by Roman numerals are set out for convenience on a separate sheet hereinafter. In this specification the term xe2x80x9calkylxe2x80x9d includes both straight and branched chain alkyl groups but references to individual alkyl groups such as xe2x80x9cpropylxe2x80x9d are specific for the straight chain version only. An analogous convention applies to other generic terms.
It is to be understood that certain aminoheterocyclic derivatives of the present invention can exist in solvate as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which possess Factor Xa inhibitory activity.
It is further to be understood that, insofar as certain of the compounds of the formula defined above may exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms, the invention encompasses any such optically active or racemic form which possesses Factor Xa inhibitory activity. The synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form.
According to a further aspect of the invention there is provided an aminoheterocyclic derivative of the formula Ia
wherein G1 is CH or N;
G2 is CH or N;
m is 1 or 2;
R1 is hydrogen, amino, halogeno, cyano, (1-4C)alkyl or (1-4C)alkoxy;
M1 is a group of the formula
NR2xe2x80x94L1xe2x80x94T1R3 
in which R2 and R3 together form a (1-4C)alkylene group,
L1 is (1-4C)alkylene, and
T1 is CH or N,
and wherein 1 or 2 methylene groups within L1 and the rings formed when R2 and R3 are linked optionally bears a (1-4C)alkyl substituent;
(1-4C)alkyl and (1-4C)alkoxy;
A is a direct link to the carbonyl group, or A is (1-4C)alkylene;
M2 is a group of the formula
(T2R4)rxe2x80x94L2xe2x80x94T3R5 
in which r is 0 or 1,
T2 is CH or N,
T3 is CH or N,
R4 is hydrogen or (1-4C)alkyl, R5 is hydrogen or (1-4C)alkyl, or R4 and R5 together form a (1-4C)alkylene, methylenecarbonyl or carbonylmethylene group, or R4 is a (2-3C)alkylene group which is linked to a methylene group within L2 forming a 5- or 6-membered ring involving R4 and T2, or R5 is a (2-3C)alkylene group which is linked to a methylene group within L2 forming a 5- or 6-membered ring involving R5 and T3,
L2 is (1-4C)alkylene, (3-6C)cycloalkane-1,2-diyl, (1-3C)alkylene-carbonyl or phenylene, and, when r is 1, L2 may also be carbonyl-(1-3C)alkylene,
and wherein 1 or 2 methylene groups within L2 and the rings formed when R4 and R5, R4 and L2 or R5 and L2 are linked optionally bears a substituent selected from the group consisting of carboxy, (1-4C)alkoxycarbonyl, carbamoyl, N-(1-4C)alkylcarbamoyl, N,N-di-(1-4C)alkylcarbamoyl, pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl, 4-(1-4C)alkylpiperazin-1-ylcarbonyl, N-phenylcarbamoyl, N-(1-4C)alkyl-N-phenylcarbamoyl, N-[phenyl-(1-3C)alkyl]carbamoyl, N-(1-4C)alkyl-N-[phenyl-(1-3C)alkyl]carbamoyl, N-[hydroxy-(2-3C)alkyl]carbamoyl, N-(1-4C)alkyl-N-[hydroxy-(2-3C)alkyl]carbamoyl, N-[(1-4C)alkoxy-(2-3C)alkyl]carbamoyl, N-(1-4C)alkyl-N-[(1-4C)alkoxy-(2-3C)alkyl]carbamoyl, N-[carboxy-(1-3C)alkyl]carbamoyl, N-(1-4C)alkyl-N-[carboxy-(1-3C)alkyl]carbamoyl, N-[carboxy-(1-3C)alkyl]-N-[hydroxy-(2-3C)alkyl]carbamoyl, N-[carboxy-(1-3C)alkyl]-N-[(1-4C)alkoxy-(2-3C)alkyl]carbamoyl, N-[(1-4C)alkoxycarbonyl-(1-3C)alkyl]carbamoyl, N-(1-4C)alkyl-N-[(1-4C)alkoxycarbonyl-(1-3C)alkyl]carbamoyl, N-[(1-4C)alkoxycarbonyl-(1-3c)alkyl]-N-[hydroxy-(2-3C)alkyl]carbamoyl, N-[(1-4C)alkoxycarbonyl-(1-3C)alkyl]-N-[(1-4C)alkoxy-(2-3C)alkyl]carbamoyl, (1-4C)alkyl, carboxy-(1-4C)alkyl, (1-4C)alkoxycarbonyl-(1-4C)alkyl, carbamoyl-(1-4C)alkyl, N-(1-4C)alkylcarbamoyl-(1-4C)alkyl, N,N-di-(1-4C)alkylcarbamoyl-(1-4C)alkyl, pyrrolidin-1-ylcarbonyl-(1-4C)alkyl, piperidinocarbonyl-(1-4C)alkyl, morpholinocarbonyl-(1-4C)alkyl, piperazin-1-ylcarbonyl-(1-4C)alkyl, 4-(1-4C)alkylpiperazin-1-ylcarbonyl-(1-4C)alkyl, N-phenylcarbamoyl-(1-4C)alkyl, N-[phenyl-(1-3C)alkyl]carbamoyl-(1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl and phenyl-(1-4C)alkyl,
and wherein any heterocyclic group in said substituent optionally bears 1 or 2 substituents selected from the group consisting of (1-4C)alkyl, (1-4C)alkoxy, carboxy, (1-4C)alkoxycarbonyl, carbamoyl, N-(1-4C)alkylcarbamoyl and N,N-di-(1-4C)alkylcarbamoyl,
and wherein any phenyl or phenylene group in M2 optionally bears 1 or 2 substituents selected from the group consisting of halogeno, trifluoromethyl, (1-4C)alkyl and (1-4C)alkoxy;
M3 is a direct link to X, or M3 is a group of the formula
L3xe2x80x94(NR6)s 
in which s is 0 or 1,
R6 is hydrogen or (1-4C)alkyl, or R5 and R6 together form a (1-4C)alkylene, methylenecarbonyl or carbonylmethylene group, or R6 is a (2-3C)alkylene group which is linked to a methylene group within L3 forming a 5- or 6-membered ring involving NR6,
L3 is (1-4C)alkylene, (3-6C)cycloalkane-1,2-diyl, carbonyl-(1-3C)alkylene or phenylene, and, when s is 1, L3 may also be (1-3C)alkylene-carbonyl,
and wherein 1 or 2 methylene groups within L3 and the rings formed when R5 and R6 or R6 and L3 are linked optionally bears a substituent selected from the group consisting of carboxy, (1-4C)alkoxycarbonyl, carbamoyl, N-(1-4C)alkylcarbamoyl, N,N-di-(1-4C)alkylcarbamoyl, pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl, 4-(1-4C)alkylpiperazin-1-ylcarbonyl, N-phenylcarbamoyl, N-(1-4C)alkyl-N-phenylcarbamoyl, N-[phenyl-(1-3C)alkyl]carbamoyl, N-(1-4C)alkyl-N-[phenyl-(1-3C)alkyl]-carbamoyl, (1-4C)alkyl, carboxy-(1-4C)alkyl, (1-4C)alkoxycarbonyl-(1-4C)alkyl, carbamoyl-(1-4C)alkyl, N-(1-4C)alkylcarbamoyl-(1-4C)alkyl, N,N-di-(1-4C)alkylcarbamoyl-(1-4C)alkyl, pyrrolidin-1-ylcarbonyl-(1-4C)alkyl, piperidinocarbonyl-(1-4C)alkyl, morpholinocarbonyl-(1-4C)alkyl, piperazin-1-ylcarbonyl-(1-4C)alkyl, 4-(1-4C)alkylpiperazin-1-ylcarbonyl-(1-4C)alkyl, N-phenylcarbamoyl-(1-4C)alkyl, N-[phenyl-(1-3C)alkyl]carbamoyl-(1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl and phenyl-(1-4C)alkyl,
and wherein any heterocyclic group in said substituent optionally bears 1 or 2 substituents selected from the group consisting of (1-4C)alkyl, (1-4C)alkoxy, carboxy, (1-4C)alkoxycarbonyl, carbamoyl, N-(1-4C)alkylcarbamoyl and N,N-di-(1-4C)alkylcarbamoyl,
and wherein any phenyl or phenylene group in M3 optionally bears 1 or 2 substituents selected from the group consisting of halogeno, trifluoromethyl, (1-4C)alkyl and (1-4C)alkoxy;
X is oxy, thio, sulphinyl, sulphonyl, carbonyl, carbonyloxy, carbonylamino, N-(1-4C)alkylcarbonylamino, sulphonylamino, methylene, (1-4C)alkylmethylene or di-(1-4C)alkylmethylene, or, when T3 is CH and
M3 is a direct link to X, X may also be aminosulphonyl or oxycarbonyl; and
Q is phenyl, naphthyl, phenyl-(1-4C)alkyl, phenyl-(2-4C)alkenyl, phenyl-(2-4C)alkynyl, (5-7C)cycloalkyl or a heterocyclic moiety containing up to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur, and Q optionally bears 1, 2 or 3 substituents selected from the group consisting of hydroxy, amino, halogeno, cyano, trifluoromethyl, nitro, carboxy, carbamoyl, formyl, formimidoyl, formohydroximoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl, (1-4C)alkoxy, N-(1-4C)alkylcarbamoyl, N,N-di-(1-4C)alkylcarbamoyl, (1-4C)alkylamino, di-(1-4C)alkylamino, (2-4C)alkanoylamino, (2-4C)alkanoyl, (2-4C)alkanoimidoyl, (2-4C)alkanohydroximoyl, phenyl, heteroaryl, phenoxy, phenylthio, phenylsulphinyl, phenylsulphonyl, heteroaryloxy, heteroarylthio, heteroarylsulphinyl, heteroarylsulphonyl, benzyl and benzoyl,
and wherein said heteroaryl substituent or the heteroaryl group in a heteroaryl-containing substituent comprises a 5- or 6-membered monocyclic heteroaryl ring containing up to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur,
and wherein said phenyl, heteroaryl, phenoxy, phenylthio, phenylsulphinyl, phenylsulphonyl, heteroaryloxy, heteroarylthio, heteroarylsulphinyl, heteroarylsulphonyl, benzyl or benzoyl substituent optionally bears 1 or 2 substituents selected from the group consisting of halogeno, trifluoromethyl, (1-4C)alkyl, (1-4C)alkoxy, hydroxy, amino, carboxy, carbamoyl, (1-4C)alkoxycarbonyl, N-(1-4C)alkylcarbamoyl, N,N-di-(1-4C)alkylcarbamoyl, (1-4C)alkylamino, di-(1-4C)alkylamino, (2-4C)alkanoylamino and tetrazolyl;
or a pharmaceutically-acceptable salt thereof.
Suitable values for the generic terms referred to above include those set out below.
When m is 2, each R1 is independently selected from hydrogen, amino, halogeno, cyano, (1-4C)alkyl and (1-4C)alkoxy.
A suitable value for R1 when it is a halogeno group, for a halogeno substituent in M2 or M3 or for a halogeno substituent in Q is, for example, fluoro, chloro, bromo or iodo.
A suitable value for R1 when it is a (1-4C)alkyl group, for a (1-4C)alkyl substituent in M1, M2 or M3 or for a (1-4C)alkyl substituent in Q is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl.
A suitable value for R1 when it is a (1-4C)alkoxy group, for a (1-4C)alkoxy-substituent in M2 or M3 or for a (1-4C)alkoxy substituent in Q is, for example, methoxy, ethoxy, propoxy, isopropoxy or butoxy.
A suitable value for R4, R5 or R6 when it is (1-4C)alkyl is, for example, methyl, ethyl, propyl, isopropyl, butyl or sec-butyl.
A suitable value for a (1-4C)alkylene group formed by R2 and R3 together, by R4 and R5 together or by R5 and R6 together is, for example, methylene, ethylene, trimethylene or tetramethylene.
A suitable value for a (2-3C)alkylene group by which R4 may be linked to a methylene group within L2, R5 may be linked to a methylene group within L2 or R6 may be linked to a methylene group within L3 is, for example, ethylene or trimethylene.
A suitable value for L1, L2 or L3 when it is (1-4C)alkylene is, for example, methylene, ethylene, trimethylene or tetramethylene; a suitable value for L2 or L3 when it is (3-6C)cycloalkane-1,2-diyl is, for example, cyclopropane-1,2-diyl, cyclobutane-1,2-diyl, cyclopentane-1,2-diyl or cyclohexane-1,2-diyl; when it is (1-3C)alkylene-carbonyl is, for example methylenecarbonyl, ethylenecarbonyl or trimethylenecarbonyl; and when it is phenylene is, for example, 1,3- or 1,4-phenylene.
A suitable value for L2 and L3 when it is carbonyl-(1-3C)alkylene is, for example, carbonylmethylene, carbonylethylene or carbonyltrimethylene.
Suitable values for the substituents which may be present within M1, M2 or M3 include, for example:
Suitable values for substituents which may be present on a heterocyclic group within a substituent which may be present within M2 or M3 include, for example:
A suitable value for A when it is (1-4C)alkylene is, for example, methylene, ethylene, trimethylene and tetramethylene.
It is to be understood that when M1 is a group of the formula
NR2xe2x80x94L1xe2x80x94T1R3 
the order of the presentation of this group is significant as to the orientation of attachment of the group. Thus it is the NR2 group which is attached to the heterocyclic group, for example, when G1 and G2 are each CH, the pyridyl group which bears the substituent R1. It is also to be understood that within the NR2 group it is the N atom which is attached to L1. Likewise the R2 group is attached to the N atom and not to the L1 group. Similarly in the T1R3 group it is the T1 group which is attached to the group A of formula I (or the CO group within formula I when A is a direct link) and the R3 group is attached to the T1 group and not to the group A of formula I. A similar convention applies to the attachment of the groups M2 and M3 and to the attachment of the T2, T3 and NR6 groups within M2 or M3.
It is further to be understood that when R4 is a (2-3C)alkylene group such as ethylene and trimethylene which is linked to a methylene group which L2 forming a 5- or 6-membered ring involving T2 and R4, a suitable ring so formed when T2 is N is, for example, pyrrolidine-1,3-diyl, piperidine-1,3-diyl and piperidine-1,4-diyl and a suitable ring so formed when T2 is CH is, for example, cyclopentane-1,3-diyl, cyclohexane-1,3-diyl and cyclohexane-1,4-diyl. Such ring systems are also suitable when, for example, R5 is linked to a methylene group within L2. Ring systems such as pyrrolidine-1,3-diyl, piperidine-1,3-diyl and piperidine-1,4-diyl are also suitable when R6 is linked to a methylene within L3.
For the avoidance of doubt it is stated that a suitable heterocyclic group in a substituent which may be present within M2 and M3 includes, for example, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl and 4-(1-4C)alkylpiperazin-1-yl whether directly attached or attached by way of a linking group as in, for example, pyrrolidin-1-ylcarbonyl-(1-4C)alkyl such as 2-(pyrrolidin-1-ylcarbonyl)ethyl.
A suitable value for X when it is a N-(1-4C)alkylcarbonylamino group is, for example, N-methylcarbonylamino or N-ethylcarbonylamino; when it is (1-4C)alkylmethylene is, for example, ethane-1,1-diyl or propane-1,1-diyl; and when it is di-(1-4C)alkylmethylene is, for example, propane-2,2-diyl. It is also to be understood that when X is a carbonyloxy, carbonylamino or N-(1-4C)alkylcarbonylamino group, it is the carbonyl group therein which is attached to M3. Likewise when X is a sulphonylamino group it is the sulphonyl group therein which is attached to M3 whereas, when X is an aminosulphonyl group, the sulphonyl group therein is attached to Q.
A suitable value for Q when it is naphthyl is, for example, 1-naphthyl or 2-naphthyl; when it is phenyl-(1-4C)alkyl is, for example, benzyl, phenethyl and 3-phenylpropyl, when it is phenyl-(2-4C)alkenyl is, for example, styryl, cinnamyl or 3-phenylprop-2-enyl; when it is phenyl-(2-4C)alkynyl is, for example, 2-phenylethynyl, 3-phenylprop-2-ynyl and 3-phenylprop-1-ynyl; and when it is (5-7C)cycloalkyl is, for example, cyclopentyl, cyclohexyl and cycloheptyl.
A suitable value for Q when it is a heterocyclic moiety containing up to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur is, for example, a 5- or 6-membered heterocyclic moiety which is a single ring or is fused to one or two benzo rings such as furyl, benzofuranyl, tetrahydrofuryl, chromanyl, thienyl, benzothienyl, pyridyl, piperidinyl, quinolyl, 1,2,3,4-tetrahydroquinolinyl, isoquinolyl, 1,2,3,4-tetrahydroisoquinolinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pyrrolyl, pyrrolidinyl, indolyl, indolinyl, imidazolyl, benzimidazolyl, pyrazolyl, indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, morpholinyl, 4H-1,4-benzoxazinyl, 4H-1,4-benzothiazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, furazanyl, thiadiazolyl, tetrazolyl, dibenzofuranyl and dibenzothienyl, which may be attached through any available position including, for an appropriate X group such as, for example, carbonyl and methylene, through any available nitrogen atom and which may bear up to three substituents including a substituent on any available nitrogen atom.
Suitable values for the substituents which may be present within Q include, for example:
A suitable value for the heteroaryl substituent or the heteroaryl group in a heteroaryl-containing substituent which comprises a 5- or 6-membered monocyclic heteroaryl ring containing up to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur is, for example, furyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, furazanyl and thiadiazolyl which may be attached through any available position including through any available nitrogen atom.
A suitable pharmaceutically-acceptable salt of an aminoheterocyclic derivative of the invention is, for example, an acid-addition salt of an aminoheterocyclic derivative of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, citric or maleic acid. In addition a suitable pharmaceutically-acceptable salt of an aminoheterocyclic derivative of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
Particular compounds of the invention include, for example, aminoheterocyclic derivatives of the formula I or of the formula Ia, or pharmaceutically-acceptable salts thereof, wherein, unless otherwise stated, each of G1, G2, G3, m, R1, M1, A, M2, M3, X and Q has any of the meanings defined hereinbefore or in this section concerning particular compounds of the invention:
(a) each of G1, G2 and G3 is CH;
(b) each of G1 and G2 is CH and G3 is N, or G1 is N and each of G2 and G3 is CH;
(c) m is 1 and R1 is hydrogen;
(d) A is a direct link to the carbonyl group;
(e) A is (1-4C)alkylene;
(f) M2 is a group of the formula
(T2R4)rxe2x80x94L2xe2x80x94T3R5 
xe2x80x83in which r is 1, T2 is CH or N, T3 is CH or N,
xe2x80x83R4 is hydrogen or (1-4C)alkyl, R5 is hydrogen or (1-4C)alkyl, or R4 and R5 together form a (1-4C)alkylene group, or R4 is a (2-3C)alkylene group which is linked to a methylene group within L2 forming a 5- or 6-membered ring involving R4 and T2, and
xe2x80x83L2 is (1-4C)alkylene,
xe2x80x83and wherein 1 or 2 methylene groups within L2 and the rings formed when R4 and R5 or R4 and L2 are linked optionally bears a substituent selected from the group consisting of carboxy, (1-4C)alkoxycarbonyl, carbamoyl, N-(1-4C)alkylcarbamoyl, N,N-di-(1-4C)alkylcarbamoyl, pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl, 4-(1-4C)alkylpiperazin-1-ylcarbonyl, N-phenylcarbamoyl, (1-4C)alkyl and phenyl-(1-4C)alkyl,
xe2x80x83and wherein any heterocyclic group in said substituent optionally bears 1 or 2 (1-4C)alkyl substituents,
xe2x80x83and wherein any phenyl group in M2 optionally bears 1 or 2 substituents selected from the group consisting of halogeno, (1-4C)alkyl and (1-4C)alkoxy;
(g) M3 is a direct link to X;
(h) M3 is a group of the formula
L3xe2x80x94(NR6)s 
xe2x80x83in which s is 1, R6 is hydrogen or (1-4C)alkyl,
xe2x80x83L3 is (1-4C)alkylene or carbonyl-(1-3C)alkylene, and wherein 1 or 2 methylene groups within L3 optionally bears a substituent selected from the group consisting of (1-4C)alkyl, hydroxy-(1-4C)alkyl and phenyl-(1-4C)alkyl,
xe2x80x83and wherein any phenyl group in M3 optionally bears 1 or 2 substituents selected from the group consisting of halogeno, (1-4C)alkyl and (1-4C)alkoxy;
(i) X is thio, sulphinyl or sulphonyl;
(j) X is sulphonyl;
(k) X is carbonyl, carbonyloxy, carbonylamino or N-(1-4C)alkylcarbonylamino;
(l) X is sulphonylamino or, when T3 is CH and M3 is a direct link to x, x may also be aminosulphonyl;
(m) X is methylene, (1-4C)alkylmethylene or di-(1-4C) alkylmethylene;
(n) Q is phenyl, naphthyl or phenyl-(1-4C)alkyl which optionally bears 1, 2 or 3 substituents selected from the group consisting of hydroxy, halogeno, cyano, trifluoromethyl, (1-4C)alkyl, (1-4C)alkoxy, phenyl, phenoxy, phenylthio, phenylsulphinyl, phenylsulphonyl, benzyl and benzoyl, and wherein the phenyl substituent or the phenyl group in a phenyl-containing substituent optionally bears 1 or 2 substituents selected from the group consisting of halogeno, (1-4C)alkyl and (1-4C) alkoxy;
(o) Q is phenyl which bears a phenyl substituent and optionally bears 1 or 2 substituents selected from the group consisting of hydroxy, halogeno, cyano, trifluoromethyl, (1-4C)alkyl and (1-4C)alkoxy, and wherein the phenyl substituent optionally bears up to 4 substituents selected from the group consisting of halogeno, trifluoromethyl, cyano, trifluoromethoxy, (1-4C)alkyl and (1-4C)alkoxy;
(p) Q is phenyl-(1-4C)alkyl, phenyl-(2-4C)alkenyl or phenyl-(2-4C)alkynyl which optionally bears 1, 2 or 3 substituents selected from the group consisting of halogeno, cyano, trifluoromethyl, (1-4C)alkyl and (1-4C)alkoxy;
(q) Q is phenyl-(2-4C)alkenyl which optionally bears 1, 2 or 3 substituents selected from the group consisting of halogeno, cyano, trifluoromethyl, (1-4C)alkyl and (1-4C)alkoxy;
(r) Q is phenyl or phenyl-(1-4C)alkyl which bears 1 substituent selected from the group consisting of heteroaryl, heteroaryloxy, heteroarylthio, heteroarylsulphinyl and heteroarylsulphonyl, wherein the heteroaryl substituent or the heteroaryl group in a heteroaryl-containing substituent comprises a 5- or 6-membered monocyclic heteroaryl ring containing up to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur, and wherein said heteroaryl or heteroaryl-containing substituent optionally bears 1 or 2 substituents selected from the group consisting of halogeno, (1-4C)alkyl and (1-4C) alkoxy;
(s) Q is phenyl which bears 1 substituent selected from the group consisting of heteroaryl, heteroaryloxy, heteroarylthio and heteroarylsulphonyl, wherein the heteroaryl substituent or the heteroaryl group in a heteroaryl-containing substituent is selected from the group consisting of thienyl, pyridyl, pyrimidinyl, pyrazolyl, oxazolyl, thiazolyl, 1,2,3-triazolyl and 1,2,4-triazolyl, and wherein said heteroaryl or heteroaryl-containing substituent optionally bears 1 or 2 substituents selected from the group consisting of halogeno and (1-4C)alkyl;
(t) Q is naphthyl which optionally bears 1 or 2 substituents selected from the group consisting of hydroxy, halogeno, cyano, trifluoromethyl, (1-4C)alkyl and (1-4C)alkoxy;
(u) Q is a heterocyclic moiety containing up to 2 heteroatoms selected from the group consisting of benzofuranyl, quinolyl, tetrahydroquinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, cinnolinyl, indolyl, benzimidazolyl, indazolyl, benzoxazolyl and benzothiazolyl, and Q optionally bears 1 or 2 substituents selected from the group consisting of halogeno, cyano, trifluromethyl, (1-4C)alkyl and (1-4C)alkoxy;
(v) Q is a heterocyclic moiety containing up to 2 heteroatoms selected from the group consisting of benzofuranyl, quinolyl, tetrahydroquinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, cinnolinyl, indolyl, benzimidazolyl, indazolyl, benzoxazolyl, benzothiazolyl, dibenzofuranyl and dibenzothienyl, and Q optionally bears 1 or 2 substituents selected from the group consisting of halogeno, cyano, trifluoromethyl, (1-4C)alkyl and (1-4C)alkoxy;
(w) Q is a heterocyclic moiety containing up to 4 heteroatoms selected from the group consisting of furyl, thienyl, pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl and tetrazolyl, and Q optionally bears 1 or 2 substituents selected from the group consisting of halogeno, cyano, carboxy, carbamoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl, (1-4C)alkoxy, N-(1-4C)alkylcarbamoyl and N,N-di-(1-4C)alkylcarbamoyl;
(x) Q is a heterocyclic moiety containing up to 2 heteroatoms selected from the group consisting of thienyl, pyridyl, pyrimidinyl, imidazolyl, pyrazolyl, oxazolyl and thiazolyl, and Q optionally bears 1 or 2 substituents selected from the group consisting of halogeno, (1-4C)alkyl, (1-4C)alkoxy, phenyl, heteroaryl, phenoxy, phenylthio, phenylsulphinyl, phenylsulphonyl, heteroaryloxy, heteroarylthio, heteroarylsulphinyl, heteroarylsulphonyl, benzyl and benzoyl, wherein the heteroaryl substituent or the heteroaryl group in a heteroaryl-containing substituent is selected from the group consisting of thienyl, pyridyl, pyrimidinyl, pyrazolyl, oxazolyl and thiazolyl, and wherein said phenyl, phenyl-containing, heteroaryl or heteroaryl-containing substituent optionally bears 1 or 2 substituents selected from the group consisting of halogeno, (1-4C)alkyl and (1-4C)alkoxy; or
(y) Q is a heterocyclic moiety containing up to 2 heteroatoms selected from the group consisting of thienyl, pyridyl, oxazolyl and thiazolyl, and Q bears a substituent selected from the group consisting of phenyl, thienyl, pyridyl, pyrimidinyl, oxazolyl and thiazolyl, which substituent optionally bears 1 or 2 substituents selected from the group consisting of halogeno, (1-4C)alkyl and (1-4C)alkoxy, and Q optionally bears a further substituent selected from the group consisting of halogeno and (1-4C)alkyl;
or a pharmaceutically-acceptable salt thereof.
A preferred compound of the invention is an aminoheterocyclic derivative of the formula I
wherein each of G1, G2 and G3 is CH, or each of G1 and G2 is CH and G3 is N, or G1 is N and each of G2 and G3 is CH;
m is 1 or 2 and each R1 is independently selected from hydrogen, amino, fluoro, chloro, bromo, cyano, methyl, ethyl and methoxy;
M1 is a group of the formula
NR2xe2x80x94Lxe2x80x94T1R3 
in which R2 and R3 together form an ethylene group,
L1 is methylene or ethylene, and T1 is CH or N,
and wherein 1 or 2 methylene groups within L1 and the ring formed when R2 and R3 are linked optionally bears a substituent selected from the group consisting of methyl and ethyl;
A is a direct link to the carbonyl group or A is methylene;
M2 is a group of the formula
(T2R4)rxe2x80x94L2xe2x80x94T3R5 
in which r is 0 or 1, T2 is CH or N, T3 is N,
R4 is hydrogen, methyl or ethyl, R5 is hydrogen, methyl or ethyl, or R4 and R5 together form a methylene, ethylene, trimethylene or methylenecarbonyl group, or R4 is an ethylene group which is linked to a methylene group within L2 forming a 5- or 6-membered ring involving R4 and T2, and
L2 is methylene, ethylene, trimethylene, methylenecarbonyl or phenylene,
and wherein 1 or 2 methylene groups within L2 and the ring formed when R4 and R5 are linked optionally bears a substituent selected from the group consisting of oxo, carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl, pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, methyl, ethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, hydroxymethyl, methoxymethyl and benzyl,
and wherein the pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl or 4-methylpiperazin-1-ylcarbonyl substituent optionally bears a methyl or ethyl substituent;
M3 is a direct link to X, or M3 is a group of the formula
L3xe2x80x94(NR6)s 
in which s is 1, R6 is hydrogen and L3 is carbonylmethylene or carbonylethylene;
X is thio, sulphinyl, sulphonyl, carbonyl, carbonyloxy or methylene; and Q is phenyl, naphthyl, benzyl, phenethyl, styryl, 2-phenylethynyl, dibenzofuranyl, biphenylyl, pyridylphenyl or pyridylthienyl, and Q optionally bears 1, 2 or 3 substituents selected from the group consisting of hydroxy, amino, fluoro, chloro, bromo, iodo, cyano, trifluoromethyl, nitro, carboxy, carbamoyl, methoxycarbonyl, ethoxycarbonyl, methyl, ethyl, methoxy and ethoxy;
or a pharmaceutically-acceptable salt thereof.
A further preferred compound of the invention is an aminoheterocyclic derivative of the formula I
wherein each of G1, G2 and G3 is CH, or each of G1 and G2 is CH and G3 is N, or G1 is N and each of G2 and G3 is CH;
m is 1 or 2 and each R1 is independently selected from hydrogen, amino, chloro, methyl and ethyl;
M1 is a group of the formula
NR2xe2x80x94L1xe2x80x94T1R3 
in which R2 and R3 together form an ethylene group,
L1 is ethylene, and
T1 is CH or N;
A is a direct link to the carbonyl group or A is methylene;
M2 is a group of the formula
(T2R4)rxe2x80x94L2xe2x80x94T3R5 
in which r is 0 or 1, T2 is N, T3 is N,
R4 is hydrogen, R5 is hydrogen, or R4 and R5 together form an ethylene group, or R4 is an ethylene group which is linked to a methylene group within L2forming a 5- or 6-membered ring involving R4 and T2, and
L2 is methylene, ethylene or phenylene,
and wherein 1 or 2 methylene groups within L2 and the ring formed when R4 and R5 are linked optionally bears a substituent selected from the group consisting of carboxy, methoxycarbonyl, ethoxycarbonyl, pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, methyl, ethyl and benzyl,
and wherein the pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl or 4-methylpiperazin-1-ylcarbonyl substituent optionally bears a methyl or ethyl substituent;
M3 is a direct link to X, or M3 is a group of the formula
L3xe2x80x94(NR6)s 
in which s is 1, R6 is hydrogen and L3 is carbonylmethylene;
X is sulphonyl; and
Q is phenyl, naphthyl, benzyl, phenethyl, styryl, 2-phenylethynyl, dibenzofuranyl, biphenylyl, pyridylphenyl or pyridylthienyl, and Q optionally bears 1 or 2 substituents selected from the group consisting of fluoro, chloro, bromo, iodo, methyl, ethyl, methoxy and ethoxy;
or a pharmaceutically-acceptable salt thereof.
A further preferred compound of the invention is an aminoheterocyclic derivative of the formula Ia
wherein each of G1 and G2 is CH;
m is 1 and R1 is hydrogen;
M1 is a group of the formula
NR2xe2x80x94L1xe2x80x94T1R3 
in which R2 and R3 together form an ethylene group,
L1 is methylene or ethylene, and
T1 is CH or N,
and wherein 1 or 2 methylene groups within L1 and the ring formed when R2 and R3 are linked optionally bears a substituent selected from the group consisting of methyl and ethyl;
A is a direct link to the carbonyl group or A is methylene;
M2 is a group of the formula
(T2R4)rxe2x80x94L2xe2x80x94T3R5 
in which r is 1, T2 is CH or N, T3 is N,
R4 is hydrogen, methyl or ethyl, R5 is hydrogen, methyl or ethyl, or R4 and R5 together form an ethylene group, or R4 is an ethylene group which is linked to a methylene group within L2 forming a 5- or 6-membered ring involving R4 and T2, and
L2 is methylene, ethylene or trimethylene,
and wherein 1 or 2 methylene groups within L2 and the ring formed when R4 and R5 are linked optionally bears a substituent selected from the group consisting of carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl, pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, methyl, ethyl and benzyl, and wherein the pyrrolidin-1-ylcarbonyl or piperidinocarbonyl substituent optionally bears a methyl or ethyl substituent;
M3 is a direct link to X, or M3 is a group of the formula
L3xe2x80x94(NR6)s 
in which s is 1, R6 is hydrogen and L3 is carbonylmethylene or carbonylethylene;
X is sulphonyl; and
Q is phenyl, 2-naphthyl or benzyl which optionally bears 1 or 2 substituents selected from the group consisting of fluoro, chloro, bromo and trifluoromethyl;
or a pharmaceutically-acceptable salt thereof.
A further preferred compound of the invention is an aminoheterocyclic derivative of the formula I
wherein G3 is CH or N and each of G1 and G2 is CH;
m is 1 and R1 is hydrogen;
M1 is a group of the formula
NR2xe2x80x94L1xe2x80x94T1R3 
in which R2 and R3 together form an ethylene group,
L1 is methylene or ethylene, and
T1 is CH or N,
and wherein 1 or 2 methylene groups within L1 and the ring formed when
R2 and R3 are linked optionally bears a substituent selected from the group consisting of methyl and ethyl;
A is a direct link to the carbonyl group or A is methylene;
M2 is a group of the formula
(T2R4)rxe2x80x94L2xe2x80x94T3R5 
in which r is 1, T2 is CH or N, T3 is N,
R4 is hydrogen, methyl or ethyl, R5 is hydrogen, methyl or ethyl, or R4 and R5 together form a methylene, ethylene or trimethylene group, or R4 is an ethylene group which is linked to a methylene group within L2 forming a 5- or 6-membered ring involving R4 and T2, and
L2 is methylene, ethylene or trimethylene,
and wherein 1 or 2 methylene groups within L2 and the ring formed when R4 and R5 are linked optionally bears a substituent selected from the group consisting of oxo, carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl, pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, methyl, ethyl and benzyl, and wherein the pyrrolidin-1-ylcarbonyl or piperidinocarbonyl substituent optionally bears one or two methyl or ethyl substituents;
M3 is a direct link to X, or M3 is a group of the formula
L3xe2x80x94(NR6)s 
in which s is 1, R6 is hydrogen and L3 is carbonylmethylene or carbonylethylene;
X is sulphonyl; and
Q is 3- or 4-biphenylyl which optionally bears, in the ring attached to X, 1 or 2 substituents selected from the group consisting of hydroxy, fluoro, chloro, bromo, cyano, trifluoromethyl, methyl, ethyl, methoxy and ethoxy and which optionally bears in the terminal phenyl group up to 4 substituents selected from the group consisting of fluoro, chloro, bromo, trifluoromethyl, cyano, trifluoromethoxy, methyl, ethyl, methoxy and ethoxy;
or a pharmaceutically-acceptable salt thereof.
A further preferred compound of the invention is an aminoheterocyclic derivative of the formula I
wherein G3 is CH or N and each of G1 and G2 is CH;
m is 1 and R1 is hydrogen;
M1 is a group of the formula
NR2xe2x80x94L1xe2x80x94T1R3 
in which R2 and R3 together form an ethylene group,
L1 is methylene or ethylene, and
T1 is CH or N,
and wherein 1 or 2 methylene groups within L1 and the ring formed when R2 and R3 are linked optionally bears a substituent selected from the group consisting of methyl and ethyl;
A is a direct link to the carbonyl group or A is methylene;
M2 is a group of the formula
(T2R4)rxe2x80x94Lxe2x80x94T3R5 
in which r is 1, T2 is CH or N, T3 is N,
R4 is hydrogen, methyl or ethyl, R5 is hydrogen, methyl or ethyl, or R4 and R5 together form a methylene, ethylene or trimethylene group, or R4 is an ethylene group which is linked to a methylene group within L2 forming a 5- or 6-membered ring involving R4 and T2, and
L2 is methylene, ethylene or trimethylene,
and wherein 1 or 2 methylene groups within L2 and the ring formed when R4 and R5 are linked optionally bears a substituent selected from the group consisting of oxo, carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl, pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, methyl, ethyl and benzyl, and wherein the pyrrolidin-1-ylcarbonyl or piperidinocarbonyl substituent optionally bears one or two methyl or ethyl substituents;
M3 is a direct link to X, or M3 is a group of the formula
L3xe2x80x94(NR6)s 
in which s is 1, R6 is hydrogen and L3 is carbonylmethylene or carbonylethylene;
X is sulphonyl; and
Q is benzyl, phenethyl, styryl or 2-phenylethynyl which optionally bears 1, 2 or 3 substituents selected from the group consisting of fluoro, chloro, bromo, cyano, trifluoromethyl, methyl, ethyl, methoxy and ethoxy;
or a pharmaceutically-acceptable salt thereof.
A further preferred compound of the invention is an aminoheterocyclic derivative of the formula Ia
wherein each of G1 and G2 is CH;
m is 1 and R1 is hydrogen;
M1 is a group of the formula
NR2xe2x80x94L1xe2x80x94T1R3 
in which R2 and R3 together form an ethylene group,
L1 is methylene or ethylene, and
T1 is CH or N,
and wherein 1 or 2 methylene groups within L1 and the ring formed when R2 and R3 are linked optionally bears a substituent selected from the group consisting of methyl and ethyl;
A is a direct link to the carbonyl group or A is methylene;
M2 is a group of the formula
(T2R4)rxe2x80x94L2xe2x80x94T3R5 
in which r is 1, T2 is CH or N, T3 is N,
R4 is hydrogen, methyl or ethyl, R5 is hydrogen, methyl or ethyl, or R4 and R5 together form an ethylene group, or R4 is an ethylene group which is linked to a methylene group within L2 forming a 5- or 6-membered ring involving R4 and T2, and
L2 is methylene, ethylene or trimethylene,
and wherein 1 or 2 methylene groups within L2 and the ring formed when R4 and R5 are linked optionally bears a substituent selected from the group consisting of carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl, pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, methyl, ethyl and benzyl, and wherein the pyrrolidin-1-ylcarbonyl or piperidinocarbonyl substituent optionally bears a methyl or ethyl substituent;
M3 is a direct link to X, or M3 is a group of the formula
L3xe2x80x94(NR6)s 
in which s is 1, R6 is hydrogen and L3 is carbonylmethylene or carbonylethylene;
X is sulphonyl; and
Q is 2-thienyl which bears a substituent selected from the group consisting of phenyl, thienyl, pyridyl and pyrimidinyl and wherein said substituents optionally bear 1 or 2 substituents selected from the group consisting of fluoro, chloro, bromo and methyl;
or a pharmaceutically-acceptable salt thereof.
A further preferred compound of the invention is an aminoheterocyclic derivative of the formula I
wherein G3 is CH or N and each of G1 and G2 is CH;
m is 1 and R1 is hydrogen;
M1 is a group of the formula
NR2xe2x80x94L1xe2x80x94T1R3 
in which R2 and R3 together form an ethylene group,
L1 is methylene or ethylene, and
T1 is CH or N,
and wherein 1 or 2 methylene groups within L1 and the ring formed when R2 and R3 are linked optionally bears a substituent selected from the group consisting of methyl and ethyl;
A is a direct link to the carbonyl group or A is methylene;
M2 is a group of the formula
(T2R4)rxe2x80x94L2xe2x80x94T3R5 
in which r is 1, T2 is CH or N, T3 is N,
R4 is hydrogen, methyl or ethyl, R5 is hydrogen, methyl or ethyl, or R4 and R5 together form an ethylene group, or R4 is an ethylene group which is linked to a methylene group within L2 forming a 5- or 6-membered ring involving R4 and T2, and
L2 is methylene, ethylene or trimethylene,
and wherein 1 or 2 methylene groups within L2 and the ring formed when R4 and R5 are linked optionally bears a substituent selected from the group consisting of carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl, pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, methyl, ethyl and benzyl, and wherein the pyrrolidin-1-ylcarbonyl or piperidinocarbonyl substituent optionally bears a methyl or ethyl substituent;
M3 is a direct link to X, or M3 is a group of the formula
L3xe2x80x94(NR6)s 
in which s is 1, R6 is hydrogen and L3 is carbonylmethylene or carbonylethylene;
X is sulphonyl; and
Q is 3- or 4-biphenylyl which optionally bears in the terminal phenyl group up to 4 substituents selected from the group consisting of fluoro, chloro, bromo, trifluoromethyl, trifluoromethoxy, methyl and methoxy;
or a pharmaceutically-acceptable salt thereof.
A further preferred compound of the invention is an aminoheterocyclic derivative of the formula I
wherein G3 is CH or N and each of G1 and G2 is CH;
m is 1 and R1 is hydrogen;
M1 is a group of the formula
NR2xe2x80x94L1xe2x80x94T1R3 
in which R2 and R3 together form an ethylene group,
L1 is methylene or ethylene, and
T1 is CH or N.
and wherein 1 or 2 methylene groups within L1 and the ring formed when R2 and R3 are linked optionally bears a substituent selected from the group consisting of methyl and ethyl;
A is a direct link to the carbonyl group or A is methylene;
M2 is a group of the formula
(T2R4)rxe2x80x94L2xe2x80x94T3R5 
in which r is 1, T2 is CH or N, T3 is N,
R4 is hydrogen, methyl or ethyl, R5 is hydrogen, methyl or ethyl, or R4 and R5 together form an ethylene group, or R4 is an ethylene group which is linked to a methylene group within L2 forming a 5- or 6-membered ring involving R4 and T2, and
L2 is methylene, ethylene or trimethylene,
and wherein 1 or 2 methylene groups within L2 and the ring formed when R4 and R5 are linked optionally bears a substituent selected from the group consisting of carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl, pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, methyl, ethyl and benzyl, and wherein the pyrrolidin-1-ylcarbonyl or piperidinocarbonyl substituent optionally bears a methyl or ethyl substituent;
M3 is a direct link to X, or M3 is a group of the formula
L3xe2x80x94(NR6)s 
in which s is 1, R6 is hydrogen and L3 is carbonylmethylene or carbonylethylene;
X is sulphonyl; and
Q is phenethyl, styryl or 2-phenylethynyl which optionally bears 1, 2 or 3 substituents selected from the group consisting of fluoro, chloro, bromo, trifluoromethyl, methyl and methoxy;
or a pharmaceutically-acceptable salt thereof.
A further preferred compound of the invention is an aminoheterocyclic derivative of the formula Ia
wherein each of G1 and G2 is CH;
m is 1 and R1 is hydrogen;
M1 is a group of the formula
NR2xe2x80x94L1xe2x80x94T1R3 
in which R2 and R3 together form an ethylene group,
L1 is ethylene, and
T1 is CH or N;
A is a direct link to the carbonyl group;
M2 is a group of formula
(T2R4)rxe2x80x94L2xe2x80x94T3R5 
in which r is 1, T2 is N and T3 is N,
R4 is hydrogen, R5 is hydrogen, or R4 and R5 together form an ethylene group, and
L2 is ethylene,
and wherein 1 methylene group within L2 optionally bears a substituent selected from carboxy, ethoxycarbonyl, N-methylcarbamoyl, piperidinocarbonyl and benzyl;
M3 is a direct link to X, or M3 is a group of the formula
L3xe2x80x94(NR6)s 
in which s is 1, R6 is hydrogen and L3 is carbonylmethylene;
X is sulphonyl; and
Q is 2-naphthyl;
or a pharmaceutically-acceptable acid-addition salt thereof.
A further preferred compound of the invention is an aminoheterocyclic derivative of the formula Ia
wherein each of G1 and G2 is CH, G1 is N and G2 is CH, or G1 is CH and G2 is N;
m is 1 and R1 is hydrogen;
M1 is a group of the formula
NR2xe2x80x94L1xe2x80x94T1R3 
in which R2 and R3 together form an ethylene group,
L1 is ethylene, and
T1 is CH or N;
A is a direct link to the carbonyl group;
M2 is a group of formula
(T2R4)rxe2x80x94L2xe2x80x94T3R5 
in which r is 1, T2 is N and T3 is N,
R4 is hydrogen, R5 is hydrogen, or R4 and R5 together form an ethylene group, and
L2 is ethylene,
and wherein 1 methylene group within L2 optionally bears a substituent selected from carboxy, ethoxycarbonyl, N-methylcarbamoyl, piperidinocarbonyl, methyl and benzyl;
M3 is a direct link to X, or M3 is a group of the formula
L3xe2x80x94(NR6)s 
in which s is 1, R6 is hydrogen and L3 is carbonylmethylene;
X is sulphonyl; and
Q is 2-naphthyl which optionally bears 1 or 2 substituents selected from the group consisting of fluoro, chloro, bromo, trifluoromethyl, methyl, methoxy and ethoxy;
or a pharmaceutically-acceptable acid-addition salt thereof.
A further preferred compound of the invention is an aminoheterocyclic derivative of the formula I
wherein each of G1, G2 and G3 is CH;
m is 1 and R1 is hydrogen;
M1 is a group of the formula
NR2xe2x80x94L1xe2x80x94T1R3 
in which R2 and R3 together form an ethylene group,
L1 is ethylene, and
T1 is CH or N;
A is a direct link to the carbonyl group;
M2 is a group of formula
(T2R4)rxe2x80x94L2xe2x80x94T3R5 
in which r is 1, T2 is N and T3 is N,
R4 is hydrogen, R5 is hydrogen, or R4 and R5 together form an ethylene group, and
L2 is ethylene,
and wherein 1 methylene group within L2 optionally bears a substituent selected from carboxy, ethoxycarbonyl, N-methylcarbamoyl, piperidinocarbonyl and benzyl;
M3 is a direct link to X, or M3 is a group of the formula
L3xe2x80x94(NR6)s 
in which s is 1, R6 is hydrogen and L3 is carbonylmethylene;
X is sulphonyl; and
Q is 4-biphenylyl which bears in the terminal phenyl group 1 or 2 substituents selected from fluoro, chloro, bromo, trifluoromethyl and methyl;
or a pharmaceutically-acceptable acid-addition salt thereof.
A further preferred compound of the invention is an aminoheterocyclic derivative of the formula I
wherein each of G1, G2 and G3 is CH, G1 is N and each of G2 and G3 is CH, or G3 is N and each of G1 and G2 is CH;
m is 1 and R1 is hydrogen;
M1 is a group of the formula
NR2xe2x80x94L1xe2x80x94T1R3 
in which R2 and R3 together form an ethylene group,
L1 is ethylene, and
T1 is CH or N;
A is a direct link to the carbonyl group;
M2 is a group of formula
(T2R4)rxe2x80x94L2xe2x80x94T3R5 
in which r is 1, T2 is N and T3 is N,
R4 is hydrogen, R5 is hydrogen, or R4 and R5 together form an ethylene group, and
L2 is ethylene,
and wherein 1 methylene group within L2 optionally bears a substituent selected from carboxy, ethoxycarbonyl, N-methylcarbamoyl, piperidinocarbonyl, methyl and benzyl;
M3 is a direct link to X, or M3 is a group of the formula
L3xe2x80x94(NR6)s 
in which s is 1, R6 is hydrogen and L3 is carbonylmethylene;
X is sulphonyl; and
Q is 4-biphenylyl which bears in the terminal phenyl group 1 or 2 substituents selected from fluoro, chloro, bromo, trifluoromethyl and methyl;
or a pharmaceutically-acceptable acid-addition salt thereof.
A further preferred compound of the invention is an aminoheterocyclic derivative of the formula I
wherein each of G1, G2 and G3 is CH;
m is 1 and R1 is hydrogen;
M1 is a group of the formula
NR2xe2x80x94L1xe2x80x94T1R3 
in which R2 and R3 together form an ethylene group,
L1 is ethylene, and
T1 is CH or N;
A is a direct link to the carbonyl group;
M2 is a group of formula
(T2R4)rxe2x80x94L2xe2x80x94T3R5 
in which r is 1, T2 is N and T3 is N,
R4 is hydrogen, R5 is hydrogen, or R4 and R5 together form an ethylene group, and
L2 is ethylene,
and wherein 1 methylene group within L2 optionally bears a substituent selected from carboxy, ethoxycarbonyl, N-methylcarbamoyl, piperidinocarbonyl and benzyl;
M3 is a direct link to X, or M3 is a group of the formula
L3xe2x80x94(NR6)s 
in which s is 1, R6 is hydrogen and L3 is carbonylmethylene;
X is sulphonyl; and
Q is styryl which optionally bears 1 or 2 substituents selected from the group consisting of fluoro, chloro, bromo, trifluoromethyl and methyl;
or a pharmaceutically-acceptable acid-addition salt thereof.
A further preferred compound of the invention is an aminoheterocyclic derivative of the formula I
wherein each of G1, G2 and G3 is CH, G1 is N and each of G2 and G3 is CH, or G3 is N and each of G1 and G2 is CH;
m is 1 and R1 is hydrogen;
M1 is a group of the formula
NR2xe2x80x94L1xe2x80x94T1R3 
in which R2 and R3 together form an ethylene group,
L1 is ethylene, and
T1 is CH or N;
A is a direct link to the carbonyl group;
M2 is a group of formula
(T2R4)rxe2x80x94L2xe2x80x94T3R5 
in which r is 1, T2 is N and T3 is N,
R4 is hydrogen, R5 is hydrogen, or R4 and R5 together form an ethylene group, and
L2 is ethylene,
and wherein 1 methylene group within L2 optionally bears a substituent selected from carboxy, ethoxycarbonyl, N-methylcarbamoyl, piperidinocarbonyl, methyl and benzyl;
M3 is a direct link to X, or M3 is a group of the formula
L3xe2x80x94(NR6)s 
in which s is 1, R6 is hydrogen and L3 is carbonylmethylene;
X is sulphonyl; and
Q is styryl which optionally bears 1 or 2 substituents selected from the group consisting of fluoro, chloro, bromo, trifluoromethyl and methyl;
or a pharmaceutically-acceptable acid-addition salt thereof.
A specific preferred compound of the invention is the following aminoheterocyclic derivative of the formula I:
2-(2-naphthalenesulphonamido)-N-{1-piperidinocarbonyl-2-[1-(4-pyridyl)-piperidin-4-ylcarbonylamino]ethyl}acetamide,
1-(2-naphthylsulphonyl)-4-[-(4-pyridyl)piperidin-4-ylcarbonyl]-piperazine,
2-(2-naphthalenesulphonamido)-N-(1-piperidinocarbonyl-2-{2-[1-(4-pyridyl)piperidin-4-yl]acetamido}ethyl)acetamide,
2-(2-naphthalenesulphonamido)-N-(1-piperidinocarbonyl-2-{2-[4-(4-pyridyl)piperazin-1-yl]acetamido}ethyl)acetamide,
ethyl 2-(2-naphthalenesulphonamido)-3-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]propionate,
1-[1-(2-naphthylsulphonyl)piperidin-4-ylcarbonyl]-4-(4-pyridyl)-piperazine or
2-(2-naphthalenesulphonamido)-N-{1-phenyl-3-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]prop-2-yl}acetamide;
or a pharmaceutically-acceptable acid-addition salt thereof.
A further specific preferred compound of the invention is the following aminoheterocyclic derivative of the formula I:
4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]-1-[(E)-styrylsulphonyl]-piperazine,
1-[(E)-4-chlorostyrylsulphonyl]-4-[-1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine,
1-[(E)-4-methylstyrylsulphonyl]-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine,
4-[(E)-4-chlorostyrylsulphonyl]-2-methyl-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine,
1-(4-biphenylylsulphonyl)-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]-piperazine,
1-(4xe2x80x2-chloro-4-biphenylylsulphonyl)-4-[1-(4-pyridyl)-piperidin-4-ylcarbonyl]piperazine or
1-[(E)-4-chlorostyrylsulphonyl]-4-[1-(4-pyrimidinyl)piperidin-4-ylcarbonyl]piperazine;
or a pharmaceutically-acceptable acid-addition salt thereof.
A further specific preferred compound of the invention is the following aminoheterocyclic derivative of the formula I:
1-(7-chloronaphth-2-ylsulphonyl)-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine,
2-ethoxycarbonyl-4-(2-naphthylsulphonyl)-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine or
1-(2-naphthylsulphonyl)-4-[1-(4-pyrimidinyl)piperidin-4-ylcarbonyl]-piperazine;
or a pharmaceutically-acceptable acid-addition salt thereof.
A further specific preferred compound of the invention is the following aminoheterocyclic derivative of the formula I:
1-[(E)-4-fluorostyrylsulphonyl]-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine,
1-[(E)-4-bromostyrylsulphonyl]-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]-piperazine or
1-(4xe2x80x2-bromo-4-biphenylylsulphonyl)-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine;
or a pharmaceutically-acceptable acid-addition salt thereof.
A further specific preferred compound of the invention is the following aminoheterocyclic derivative of the formula I:
1-(6-chloronaphth-2-ylsulphonyl)-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine,
1-(6-bromonaphth-2-ylsulphonyl)-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine,
1-(6-chloronaphth-2-ylsulphonyl)-4-[4-(4-pyridyl)piperazin-1-ylcarbonyl]piperazine,
4-(2-naphthylsulphonyl)-2-piperidinocarbonyl-1-[1-(4-pyridyl)-piperidin-4-ylcarbonyl]piperazine,
4-(6-chloronaphth-2-ylsulphonyl)-2-ethoxycarbonyl-1-[1-(4-pyridyl)-piperidin-4-ylcarbonyl]piperazine,
2-carboxy-4-(6-chloronaphth-2-ylsulphonyl)-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine,
1-(6-chloronaphth-2-ylsulphonyl)-4-[1-(4-pyrimidinyl)piperidin-4-ylcarbonyl]piperazine,
4-[1-(2-aminopyrimidin-4-yl)piperidin-4-ylcarbonyl]-1-(6-chloronaphth-2-ylsulphonyl)piperazine or
1-(6-chloronaphth-2-ylsulphonyl)-4-[1-(4-pyridazinyl)piperidin-4-ylcarbonyl]piperazine;
or a pharmaceutically-acceptable acid-addition salt thereof.
A further specific preferred compound of the invention is the following aminoheterocyclic derivative of the formula I:
4-(6-bromonaphth-2-ylsulphonyl)-2-ethoxycarbonyl-1-[1-(4-pyridyl)-piperidin-4-ylcarbonyl]piperazine,
4-(6-bromonaphth-2-ylsulphonyl)-2-carboxy-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine,
4-(6-bromonaphth-2-ylsulphonyl)-2-morpholinocarbonyl-1-[1-(4-pyridyl)-or piperidin-4-ylcarbonyl]piperazine,
4-(6-chloronaphth-2-ylsulphonyl)-2-methoxycarbonyl-1-[1-(4-pyridyl)-piperidin-4-ylcarbonyl]piperazine or
2-carboxy-4-(6-chloronaphth-2-ylsulphonyl)-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine;
or a pharmaceutically-acceptable salt thereof.
An aminoheterocyclic derivative of the formula I or of the formula Ia, or a pharmaceutically-acceptable salt thereof, may be prepared by any process known to be applicable to the preparation of structurally-related compounds. Such procedures are provided as a further feature of the invention and are illustrated by the following representative processes in which, unless otherwise stated G1, G2, G3, m, R1, M1, A, M2, M3, X and Q (and any groups defined therein) have any of the meanings defined hereinbefore, provided that when there is an amino, alkylamino, hydroxy or carboxy group in R1, M1, M2, M3 or Q then any such group is protected by a conventional protecting group which may be removed when so desired by conventional means.
Necessary starting materials may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is illustrated within the accompanying Examples; alternatively analogous procedures to those illustrated may be employed by applying no more than the ordinary skill of an organic chemist.
(a) For the production of those compounds of the formula I wherein M2 is a group of the formula
(T2R4)rxe2x80x94L2xe2x80x94T3R5 
in which T2 is N and r is 1, the reaction, conveniently in the presence of a suitable base, of an acid of the formula II, or a reactive derivative thereof, with an amine of the formula
HNR4xe2x80x94L2xe2x80x94T3R5xe2x80x94M3xe2x80x94Xxe2x80x94Q 
A suitable reactive derivative of an acid of the formula II is, for example, an acyl halide, for example an acyl chloride formed by the reaction of the acid and an inorganic acid chloride, for example thionyl chloride; a mixed anhydride, for example an anhydride formed by the reaction of the acid and a chloroformate such as isobutyl chloroformate; an active ester, for example an ester formed by the reaction of the acid and a phenol such as pentafluorophenol, an ester such as pentafluorophenyl trifluoroacetate or an alcohol such as N-hydroxybenzotriazole or N-hydroxysuccinimide; an acyl azide, for example an azide formed by the reaction of the acid and an azide such as diphenylphosphoryl azide; an acyl cyanide, for example a cyanide formed by the reaction of an acid and a cyanide such as diethylphosphoryl cyanide; or the product of the reaction of the acid and a carbodiimide such as N,Nxe2x80x2-dicyclohexylcarbodiimide or N-(3-dimethylaminopropyl)-Nxe2x80x2-ethylcarbodiimide.
The reaction is conveniently carried out in the presence of a suitable base such as, for example, an alkali or alkaline earth metal carbonate, alkoxide, hydroxide or hydride, for example sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride, or an organometallic base such as an alkyl-lithium, for example n-butyl-lithium, or a dialkylamino-lithium, for example lithium di-isopropylamide, or, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine or diazabicyclo-[5.4.0]undec-7-ene. The reaction is also preferably carried out in a suitable inert solvent or diluent, for example methylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethylsulphoxide or acetone, and at a temperature in the range, for example, xe2x88x9278xc2x0 to 150xc2x0 C., conveniently at or near ambient temperature.
A suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid such as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a tert-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
(b) For the production of those compounds of the formula I wherein M2 is a group of the formula
(T2R4)rxe2x80x94L2xe2x80x94T3R5 
in which T3 is N,
and wherein M3 is a direct link to X,
the reaction, conveniently in the presence of a suitable base as defined hereinbefore, of an amine of the formula III with a compound of the formula Zxe2x80x94Xxe2x80x94Q wherein Z is a displaceable group.
A suitable value for the displaceable group Z is, for example, a halogeno or sulphonyloxy group, for example a fluoro, chloro, bromo, mesyloxy or 4-tolylsulphonyloxy group.
The reaction is conveniently performed in a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 0xc2x0 C. to 150xc2x0 C., conveniently at or near ambient temperature.
(c) For the production of those compounds of the formula I wherein M1 is a group of the formula
NR2xe2x80x94L1xe2x80x94T1R3 
in which T1 is N,
and wherein A is a direct link to the carbonyl group,
the reaction, conveniently in the presence of a suitable base as defined hereinbefore, of an amine of the formula IV with an acid of the formula
HO2Cxe2x80x94M2xe2x80x94M3xe2x80x94Xxe2x80x94Q 
or a reactive derivative thereof as defined hereinbefore.
The reaction is conveniently performed in a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 0xc2x0 to 150xc2x0 C., conveniently at or near ambient temperature.
(d) For the production of those compounds of the formula I wherein M2 is a group of the formula
(T2R4)rxe2x80x94L2xe2x80x94T3R5 
in which T3 is N,
and wherein M3 is a group of the formula
L3xe2x80x94(NR6)s 
in which L3 is carbonylmethylene,
the reaction, conveniently in the presence of a suitable base as defined hereinbefore, of an amine of the formula III with an acid of the formula
HO2Cxe2x80x94CH2xe2x80x94(NR6)sxe2x80x94Xxe2x80x94Q 
or a reactive derivative thereof as defined hereinbefore.
The reaction is conveniently performed in a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 0xc2x0 to 150xc2x0 C., conveniently at or near ambient temperature.
(e) For the production of those compounds of the formula I wherein M2 is a group of the formula
(T2R4)rxe2x80x94L2xe2x80x94T3R5 
in which T3 is N,
and wherein M3 is a direct link to X and X is carbonylamino,
the reaction of an amine of the formula III with an isocyanate of the formula
OCNxe2x80x94Xxe2x80x94Q 
The reaction is conveniently performed in a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 0xc2x0 to 60xc2x0 C., conveniently at or near ambient temperature.
(f) The reaction, conveniently in the presence of a suitable base as defined hereinbefore, of a compound of the formula V wherein Z is a displaceable group as defined hereinbefore, with an amine of the formula
HNR2xe2x80x94L1xe2x80x94T1R3xe2x80x94Axe2x80x94COxe2x80x94M2xe2x80x94M3xe2x80x94Xxe2x80x94Q 
The reaction is conveniently performed in a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 0xc2x0 to 150xc2x0 C., conveniently in the range 15xc2x0 to 100xc2x0 C.
(g) For the production of those compounds of the formula I wherein M2, M3 or Q bears a carboxy or carboxy-containing group, the hydrolysis of a compound of the formula I wherein M2, M3 or Q bears a (1-4C)alkoxycarbonyl group.
The hydrolysis reaction may conveniently be carried out in a conventional manner using, for example acidic or basic catalysis. A suitable acid for the acidic hydrolysis of an ester group is, for example, an inorganic acid such as hydrochloric or sulphuric acid. A suitable base for the basic hydrolysis of an ester group is, for example, an alkali or alkaline earth metal hydroxide such as sodium hydroxide or potassium hydroxide.
The reaction is conveniently performed in a suitable solvent or diluent such as an alcohol, for example methanol or ethanol, and at a temperature in the range, for example, 0xc2x0 to 120xc2x0 C., conveniently in the range of 15xc2x0 to 60xc2x0 C.
(h) For the production of those compounds of the formula I wherein M2, M3 or Q bears a carbamoyl, N-alkylcarbamoyl or N,N-dialkylcarbamoyl group, the reaction of a compound of the formula I wherein M2, M3 or Q bears a carboxy group, or a reactive derivative thereof as defined hereinbefore, with ammonia or an appropriate alkylamine or dialkylamine.
The reaction is conveniently performed in a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 0xc2x0 to 120xc2x0 C., conveniently in the range 15xc2x0 to 60xc2x0 C.
(i) For the production of those compounds of the formula I wherein Q bears a hydroxy group, the dealkylation of a compound of the formula I wherein Q bears a (1-4C)alkoxy group.
A suitable dealkylating reagent is, for example, any of the many reagents known to effect such a transformation. The reaction may be carried out, for example, using an alkali metal (1-4C)alkylsulphide such as sodium ethanethiolate or, for example, using an alkali metal diarylphosphide such as lithium diphenylphosphide. Alternatively the reaction may conveniently be carried out using a boron or aluminium trihalide such as boron tribromide.
The dealkylation reaction is conveniently performed in a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, xe2x88x9280xc2x0 to 100xc2x0 C., conveniently in the range 0xc2x0 to 50xc2x0 C.
When a pharmaceutically-acceptable salt of a compound of the formula I is required, it may be obtained, for example, by reaction of said compound with a suitable acid or base using a conventional procedure.
When an optically active form of a compound of the formula I is required, it may be obtained, for example, by carrying out one of the aforesaid procedures using an optically active starting material or by resolution of a racemic form of said compound using a conventional procedure.
As stated previously, the compounds of the formula I and of the formula Ia are inhibitors of the enzyme Factor Xa. The effects of this inhibition may be demonstrated using one or more of the standard procedures set out hereinafter:
a) Measurement of Factor Xa Inhibition
An in vitro assay system was carried out based on the method of Kettner et al., J. Biol. Chem., 1990, 265, 18289-18297, whereby various concentrations of a test compound were dissolved in a pH7.5 buffer containing 0.5% of polyethylene glycol and incubated at 37xc2x0 C. with human Factor Xa (0.001 Units/ml, 0.3 ml) for 15 minutes. The chromogenic substrate S-2765 (KabiVitum AB, 20 xcexcM) was added and the mixture was incubated at 37xc2x0 C. for 20 minutes whilst the absorbance at 405 nm was measured. The maximum reaction velocity (Vmax) was determined and compared with that of a control sample containing no test compound. Inhibitor potency was expressed as an IC50 value.
b) Measurement of Thrombin Inhibition
The procedure of method a) was repeated except that human thrombin (0.005 Units/ml) and the chromogenic substrate S-2238 (KabiVitum AB) were employed.
c) Measurement of Anticoagulant Activity
An in vitro assay whereby human venous blood was collected and added directly to a sodium citrate solution (3.2 g/100 ml, 9 parts blood to 1 part citrate solution). Blood plasma was prepared by contrifugation (1000 g, 15 minutes) and stored at 2-4xc2x0 C. Conventional activated partial thromboplastin time (APTT) and prothrombin time (PT) tests were carried out in the presence of various concentrations of a test compound and the concentration of test compound required to double the clotting time, hereinafter referred to as CT2, was determined. In the APTT test, the test compound, blood plasma and APTT reagent were incubated at 37xc2x0 C. for 3 minutes. Calcium chloride (0.02M) was added and fibrin formation and the time required for a clot to form were determined. In the PT test, an analogous procedure was followed except that tissue thromboplastin was used in place of APTT reagent.
d) An ex vivo Assay of Anticoagulant Activity
The test compound was administered intravenously or orally to a group of Alderley Park Wistar rats. At various times thereafter animals were anaesthetised, blood was collected and APTT and PT coagulation assays analogous to those described hereinbefore were conducted.
e) An in vivo Measurement of Antithrombotic Activity
Thrombus formation was induced using an analogous method to that described by Vogel et al., Thromb. Research, 1989, 54, 399-410. A group of Alderley Park Wistar rats was anaesthetised and surgery was performed to expose the vena cava. Two loose sutures were located, 0.7 cm apart, round the inferior vena cava. Test compound was administered intravenously or orally. At an appropriate time thereafter tissue thromboplastin (1 ml/kg) was administered into the jugular vein and, after 10 seconds, the two sutures were tightened to induce stasis within the ligated portion of vena cava. After 10 minutes the ligated tissue was excised and the thrombus therein was isolated, blotted and weighed.
Although the pharmacological potencies of the compounds of formulae I and Ia vary with structural changes as expected, in general compounds of the formulae I and Ia possess activity at the following concentrations or doses in at least one of the above tests a) to c):
test a): IC50 (Factor Xa) in the range, for example, 0.001-25 xcexcM;
test b): IC50 (thrombin), for example, greater than 50 xcexcM;
test c): CT2 (PT) in the range, for example, 1-50 xcexcM; CT2 (APTT) in the range, for example, 10-100 xcexcM.
By way of example, the compound of Example 1 as disclosed hereinafter has an IC50 of 0.3 xcexcM against Factor Xa in test a), an IC50 of greater than 100 xcexcM against thrombin in test b) and a CT2 (PT) of 14 xcexcM and CT2 (APTT) of 62 xcexcM in test c), and shows an increased clotting time following the intravenous administration of a 10 mg/kg dose in test d) and a reduced thrombus weight following the intravenous administration of a 5 mg/kg dose in test e).
By way of further example, the compound of Example 39, Compound No. 2, as disclosed hereinafter has an IC50 of 0.012 xcexcM against Factor Xa in test a), an IC50 of greater than 100 xcexcM against thrombin in test b), a CT2 (PT) of 1 xcexcM and CT2 (APTT) of 1.8 xcexcM in test c), and shows an increased clotting time following the intravenous administration of a 5 mg/kg dose in test d) and a reduced thrombus weight following the intravenous administration of a 5 mg/kg dose in test d).
By way of further example, the compound of Example 41, Compound No. 3, as disclosed hereinafter has an IC50 of 0.01 xcexcM against Factor Xa in test a) and an IC50 of 83 xcexcM against thrombin in test b).
By way of further example, the compound of Example 40, Compound No. 5, as disclosed hereinafter has an IC50 of 0.003 xcexcM against Factor Xa in test a), an IC50 of 34 xcexcM against thrombin in test b), a CT2 (PT) of 0.5 xcexcM and CT2 (APTT) of 1.2 xcexcM in test c), and shows an increased clotting time following the intravenous administration of a 5 mg/kg dose in test d).
By way of further example, the compound of Example 62 as disclosed hereinafter has an IC50 of 0.002 xcexcM against Factor Xa in test a), an IC50 of  greater than 10 xcexcM against thrombin in test b), a CT2 (PT) of 0.7 xcexcM in test c), and shows an increased clotting time following the intravenous administration of a 5 mg/kg dose in test d).
By way of further example, the compound of Example 63 as disclosed hereinafter has an IC50 of 0.008 xcexcM against Factor Xa in test a), an IC50 of  greater than 10 xcexcM against thrombin in test b), a CT2 (PT) of 4.6 xcexcM in test c), and shows an increased clotting time following the intravenous administration of a 5 mg/kg dose in test d) and a reduced thrombus weight following the intravenous administration of a 5 mg/kg dose in test e).
According to a further feature of the invention there is provided a pharmaceutical composition which comprises an aminoheterocyclic derivative of the formula I or of the formula Ia, or a pharmaceutically-acceptable salt thereof, in association with a pharmaceutically-acceptable diluent or carrier.
The composition may be in a form suitable for oral use, for example a tablet, capsule, aqueous or oily solution, suspension or emulsion; for topical use, for example a cream, ointment, gel or aqueous or oily solution or suspension; for nasal use, for example a snuff, nasal spray or nasal drops; for vaginal or rectal use, for example a suppository; for administration by inhalation, for example as a finely divided powder such as a dry powder, a microcrystalline form or a liquid aerosol; for sub-lingual or buccal use, for example a tablet or capsule; or for parenteral use (including intravenous, subcutaneous, intramuscular, intravascular or infusion), for example a sterile aqueous or oily solution or suspension. In general the above compositions may be prepared in a conventional manner using conventional excipients.
The amount of active ingredient (that is an aminoheterocyclic derivative of the formulae I or Ia, or a pharmaceutically-acceptable salt thereof) that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition. Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient.
According to a further feature of the invention there is provided an aminoheterocyclic derivative of the formula I or of the formula Ia, or a pharmaceutically-acceptable salt thereof, for use in a method of treatment of the human or animal body by therapy.
The invention also includes the use of such an active ingredient in the production of a medicament for use in:
(i) producing a Factor Xa inhibitory effect;
(ii) producing an anticoagulant effect;
(iii) producing an antithrombotic effect;
(iv) treating a Factor Xa mediated disease or medical condition;
(v) treating a thrombosis mediated disease or medical condition;
(vi) treating coagulation disorders; and/or
(vii) treating thrombosis or embolism involving Factor Xa mediated coagulation.
The invention also includes a method of producing an effect as defined hereinbefore or treating a disease or disorder as defined hereinbefore which comprises administering to a warm-blooded animal requiring such treatment an effective amount of an active ingredient as defined hereinbefore.
The size of the dose for therapeutic or prophylactic purposes of a compound of the formulae I or Ia will naturally vary according to the nature and severity of the medical condition, the age and sex of the animal or patient being treated and the route of administration, according to well known principles of medicine. As mentioned above, compounds of the formulae I or Ia are useful in the treatment or prevention of a variety of medical disorders where anticoagulant therapy is indicated. In using a compound of the formula I for such a purpose, it will generally be administered so that a daily dose in the range, for example, 0.5 to 500 mg/kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed, for example a dose for intravenous administration in the range, for example, 0.5 to 50 mg/kg body weight will generally be used. For preferred and especially preferred compounds of the invention, in general, lower doses will be employed, for example a daily dose in the range, for example, 0.5 to 10 mg/kg body weight.
Although the compounds of the formulae I and Ia are primarily of value as therapeutic or prophylactic agents for use in warm-blooded animals including man, they are also useful whenever it is required to produce an anticoagulant effect, for example during the ex-vivo storage of whole blood or in the development of biological tests for compounds having anticoagulant properties.
The compounds of the invention may be administered as a sole therapy or they may be administered in conjunction with other pharmacologically active agents such as a thrombolytic agent, for example tissue plasminogen activator or derivatives thereof or streptokinase. The compounds of the invention may also be administered with, for example, a known platelet aggregation inhibitor (for example aspirin, a thromboxane antagonist or a thromboxane synthase inhibitor), a known hypolipidaemic agent or a known anti-hypertensive agent.
The invention will now be illustrated in the following Examples in which, unless otherwise stated:
(i) evaporations were carried out by rotary evaporation in vacuo and work-up procedures were carried out after removal of residual solids by filtration;
(ii) operations were carried out at room temperature, that is in the range 18-25xc2x0 C. and under an atmosphere of an inert gas such as argon;
(iii) column chromatography (by the flash procedure) and medium pressure liquid chromatography (MPLC) were performed on Merck Kieselgel silica (Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) reversed-phase silica obtained from E. Merck, Darmstadt, Germany;
(iv) yields are given for illustration only and are not necessarily the maximum attainable;
(v) the end-products of the formula I have satisfactory microanalyses and their structures were confirmed by nuclear magnetic resonance (NMR) and mass spectral techniques; unless otherwise stated, CDCl3 solutions of the end-products of the formula I were used for the determination of NMR spectral data, chemical shift values were measured on the delta scale; the following abbreviations have been used: s, singlet; d, doublet; t, triplet; m, multiplet;
(vi) intermediates were not generally fully characterised and purity was assessed by thin layer chromatographic, infra-red (IR) or NMR analysis;
(vii) melting points were determined using a Mettler SP62 automatic melting point apparatus or an oil-bath apparatus; melting points for the end-products of the formula I were generally determined after crystallisation from a conventional organic solvent such as ethanol, methanol, acetone, ether or hexane, alone or in admixture; and
(viii) the following abbreviations have been used: